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Review
. 2021 Sep 30;10(10):2603.
doi: 10.3390/cells10102603.

The Intersection of Purine and Mitochondrial Metabolism in Cancer

Humberto De Vitto  1 , Danushka B Arachchige  1 , Brian C Richardson  1 , Jarrod B French  1
Affiliations
Review

The Intersection of Purine and Mitochondrial Metabolism in Cancer

Humberto De Vitto et al. Cells. .

Abstract

Nucleotides are essential to cell growth and survival, providing cells with building blocks for DNA and RNA, energy carriers, and cofactors. Mitochondria have a critical role in the production of intracellular ATP and participate in the generation of intermediates necessary for biosynthesis of macromolecules such as purines and pyrimidines. In this review, we highlight the role of purine and mitochondrial metabolism in cancer and how their intersection influences cancer progression, especially in ovarian cancer. Additionally, we address the importance of metabolic rewiring in cancer and how the evolving landscape of purine synthesis and mitochondria inhibitors can be potentially exploited for cancer treatment.

Keywords: amino acids; cancers; metabolic reprogramming; mitochondrial metabolism; purines.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Purine metabolic pathways. The schematic representation shows the de novo and salvage pathways and their crosstalk with mitochondria. The conserved de novo biosynthesis pathway to generate IMP consists of 10 chemical steps catalyzed by 6 gene products in humans. These include the trifunctional enzyme TGART, composed of GAR synthetase (GARS), GAR transformylase (GARTfase), and AIR synthetase (AIRS) domains; the bifunctional enzymes PAICS, composed of CAIR synthetase/AIR carboxylase (CAIRS) and SAICAR synthetase (SAICARS), and ATIC, composed of AICAR transformylase (AICART) and IMP cyclohydrolase (IMPCH); and three monofunctional enzymes, phosphoribosyl amidotransferase (PPAT), formylglycinamidine ribonucleotide synthetase (FGAMS), and adenylosuccinate lyase (ADSL). Downstream IMP is converted to (1) GMP through stepwise reactions of IMP dehydrogenase (IMPDH) followed by GMP synthetase (GMPS) and (2) AMP via adenylosuccinate synthetase (ADSS) followed by ADSL. The salvage pathway requires PRPP to generate IMP and GMP through one-step reactions mediated by hypoxanthine phosphoribosyltransferase (HPRT) utilizing hypoxanthine and guanine bases. AMP is generated by adenine phosphoribosyltransferase (APRT) utilizing adenine base and PRPP as substrates. Mitochondria supply precursors for purine de novo biosynthesis including glycine, N10-formyl THF, and aspartic acid through their one-carbon cycle (1C cycle) and tricarboxylic acid cycle (TCA).
Figure 2
Figure 2
Interconnectivity of purine metabolism. The schematic representation illustrates how proliferative cells use nutrient availability and metabolic networks that feed into, are regulated by or otherwise integrated with purine metabolism. Key reactions in central metabolism are shown, including how glucose, glutamine, serine/glycine, one-carbon, and mitochondrial metabolism are involved in the de novo purine biosynthesis.
Figure 3
Figure 3
Targeted metabolic inhibitors. The schematic representation shows the metabolic vulnerabilities of cancer. The identification of rational combinations of mitochondrial inhibitors with the standard of care treatment including folate and purine antagonists may bring new insights for cancer treatment. FDA-approved drugs to treat cancer are indicated in red, and drugs under study or in clinical trials are indicated in blue. The identification of novel biomarkers and drug targets to improve the detection and treatment of cancers by modulating purine metabolism is now subject to investigation in several research programs.
See this image and copyright information in PMC

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